In cancer chemotherapies, some chemotherapeutic agents are given systemically and exert their anti-cancer effects by exploiting differential metabolic or regulatory activity of cancer cells compared to non-cancer cells. The approach results in side effects including toxicity and immune suppression. Alternative approaches take advantage of differential receptor expression on cancer cells and use agonistic antibodies to initiate pro-death signaling pathways within cancer cells. However, transformed cells typically have defects in the response to pro-apoptotic stimuli. As a result of their general unresponsiveness to pro-apoptotic stimuli, many types of cancer cells are remarkably sensitive to slight perturbations in the balance between pro- and anti-apoptotic proteins. Furthermore, targeted therapies such as radiation and surgery are by their nature blind to distant metastases.
Many pharmaceuticals, such as chemotherapeutic agents, can be highly toxic to normal cells. Selective delivery of a pharmaceutical compound to a target cell population can therefore be advantageous (Schally and Nagy, European Journal of Endocrinology 141: 1-14, 1999). For example, cytotoxic peptide conjugates comprising both a peptide carrier which binds to a target receptor on tumor cells and a small molecule cytotoxic moiety such as doxorubicin, have been reported (Id.) Other strategies have been proposed or developed to target tumors. These strategies include physical targeting with radiation (Leibel, S. A., Semin. Oncol. 30: 596-615, 2003), physical targeting with intratumoral injection (Kashiwagi, H., et al., Ann. Surg. Oncol. 14: 1763-1771, 2007) targeting of receptors with antibodies (Kumar, P. S., et al., Semin. Oncol. 33: 386-391, 2006; Pangalis, G. A., et al., Curr. Topics Med. Chem. 6: 1657-1686, 2006), targeting receptors with ligands (MacFarlane, M., et al., Cell Death Differ. 12: 773-82, 2005), administering prodrugs that are activated by enzymes which are active in the local milieu (Kline, T., et al., Mol. Pharm. 1: 9-22, 2004) and exploiting differences in metabolic needs (Ippolito, J., et al., Proc Natl Acad Sci USA 103: 12505-12510, 2006; Nakajima, M., et al., Nippon Yakurigaku Zasshi 122: 482-490, 2003).
Programmed cell death or apoptosis is an essential process in cell homeostasis and eukaryotic development (Prochazkova, J. et al., Gen. Physiol. Biophys. 23: 209-229, 2004; Danial, N. N., et al., Cell 116: 205-219, 2004). Therefore, there is considerable interest in targeting the molecular pathways of apoptosis as a component of cancer therapy. Recent studies have shown that failure of apoptosis is both central to the evolution of cancer and related to resistance toward modern adjuvant treatment such as chemo- or radiation therapies (Debatin, K. M., et al., Oncogene 23: 2950-2966, 2004; Bergman, P. J., et al., Vet. Clin. North Amer. Small Animal Pract. 27: 47-57 1997; Tan, T. T., et al., Cancer Cell 7: 227-238, 2005). We and others have recently reported that intracellular delivery of pro-apoptotic peptides can induce apoptosis in cancer cells in vitro and in animal models of adenocarcinomas in vivo (Guelen, L., et al., Oncogene 23: 1153-1165, 2004; Ryu, J., et al., Mol. Cells. 17: 353-359, 2004; Kashiwagi, H., et al., Ann. Surg. Oncol. 14: 1763-1771, 2007; Schwarze, S. R., Science 285: 1569-1572, 1999). For example, TAT-Bim is a dual domain peptide molecule comprised of an internalization peptide motif (the polybasic region of HIV-1 TAT) and a biological effector peptide domain (the apoptosis-inducing BH3 domain of Bim). Anti-tumor effectiveness of such compounds in vivo could be demonstrated by injecting them intra-tumorally due to the non-specific cell permeation capacity of the TAT peptide (Schwarze, S. R., Science 285: 1569-1572, 1999). Direct intra-tumoral injection of the TAT-Bim compound effectively reduced tumor size and prolonged survival in animal models of pancreatic cancer (Kashiwagi, H., Ann. Surg. Oncol. 14: 1763-1771, 2007).
Each of these various approaches has inherent limitations; for example, physical targeting has no ability to treat distant metastases, and antibody-based targeting approaches can be hampered by barriers to accessibility of a macromolecular carrier. Accordingly, new approaches are needed.